Research Article: Association between MICA polymorphisms, s-MICA levels, and pancreatic cancer risk in a population-based case-control study

Date Published: June 5, 2019

Publisher: Public Library of Science

Author(s): Guillaume Onyeaghala, John Lane, Nathan Pankratz, Heather H. Nelson, Bharat Thyagarajan, Bruce Walcheck, Kristin E. Anderson, Anna E. Prizment, Narasimha Reddy Parine.

http://doi.org/10.1371/journal.pone.0217868

Abstract

Pancreatic tumor cells may avoid immune surveillance by releasing the transmembrane major histocompatibility complex class I chain-related A (MICA) protein in soluble form (s-MICA). We hypothesized that the presence of the A5.1 polymorphism in the MICA gene, which encodes a truncated MICA protein, is associated with higher s-MICA levels and increased pancreatic cancer risk.

MICA alleles and s-MICA levels were measured in 121 pancreatic cancer cases and 419 controls. General linear regression with a log transformation assessed geometric means of s-MICA levels across MICA alleles. Unconditional logistic regression was used to calculate the odds ratio (OR) and 95% confidence intervals (CI) for pancreatic cancer associated with MICA alleles.

After multivariate adjustment, participants with at least one copy of the A5.1 allele versus no A5.1 allele had 1.35 (95% CI: 1.05–1.74) times greater s-MICA levels (1.65 times higher for cases and 1.28, for controls) and increased risk of pancreatic cancer (OR = 1.91, 95% CI: 1.05–3.48).

Our study suggests higher risk of pancreatic cancer among those with the MICA A5.1 polymorphism, which may be explained by an increase in s-MICA secretion and impaired immune response.

These findings provide further evidence at the genetic and molecular level of the important role of MICA in pancreatic cancer development, and may have important implications with regards to pancreatic cancer screening.

Partial Text

Pancreatic cancer is the 4th leading cause of cancer death among men and women in the U.S., with over 40,000 deaths annually[1]. Currently, there are no screening tests to detect pancreatic cancer at an early stage. [2,3] Most pancreatic cancer patients are diagnosed at an advanced stage when benefits of treatment are very limited and thus most cases have an extremely poor prognosis, with a 9% five-year survival rate[1]. Therefore, there is an urgent need for new methods for early detection and treatment of pancreatic cancer. Emerging evidence shows that the immune system plays an important role in the pathogenesis of pancreatic cancer[4,5]. Understanding specific immune system mechanisms that interact with pancreatic tumor cells could help determine high-risk groups who may benefit from screening and lead to new therapies in the future.

The median age of the 540 participants in this study was 68 years, and 44% were female (Table 1). Participants with pancreatic cancer were more likely to smoke (18% vs. 12%; p = 0.02) and report a history of diabetes (21% vs 8%, p = <0.01), but they were less likely to drink alcohol (11% vs. 18%; p = <0.01) or be college educated (47% vs 60%, p = <0.01) compared to controls (Table 1). The observed frequency of the MICA A5.1 allele was 73% (n = 396), with 155 participants being homozygous and 241 participants being heterozygous for MICA A5.1 (Fig 1). In this population-based case-control study, we found that having at least one copy of the MICA A5.1 allele was associated with an increased risk of pancreatic cancer. We also showed that participants with the MICA A5.1 allele had elevated circulating levels of s-MICA, in both controls and pancreatic cancer cases, with higher levels in the cases. This finding is in line with our previous findings of an association between elevated s-MICA levels and increased pancreatic cancer risk[31]. In addition, we reported that the association between the MICA A5.1 allele and pancreatic cancer disappeared after adjusting for s-MICA levels implying that the s-MICA was on causal pathway between MICA A5.1 allele and pancreatic cancer.   Source: http://doi.org/10.1371/journal.pone.0217868